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PubMed2003

Epigenetic transitions: towards therapeutic targets.

Therapeutic approaches aimed at developing epigenetically-effective drugs are under intense investigation. Several classes of enzymes regulating histone acetylation and DNA methylation, which are required for epigenetic transitions, offer attractive targets for therapeutic interventions. Imbalances in histone acetylation and DNA methylation may play a significant role in the development of cancer and leukaemia and may provide a mechanistic rationale for targeting epigenetic modifications. Clinical trials designed to evaluate inhibitors of DNA methylation and histone deacetylase inhibitors are showing encouraging results in cancer patients. A growing quantity of data from preclinical research supports the notion that epigenetically-effective drugs could also find an application in other therapeutic areas. A number of emerging biomarkers may prove useful for monitoring drug effects and defining molecular signatures of response, toxicity and effective dose.

Acetylation↗

PubMed2005

Epigenetic regulation of the cell type-specific gene 14-3-3sigma.

Epigenetic control participates in processes crucial in mammalian development, such as X-chromosome inactivation, gene imprinting, and cell type-specific gene expression. We provide evidence that the p53-inducible gene 14-3-3sigma is a new example of a gene important to human cancer, where epigenetic mechanisms participate in the control of normal cell type-specific expression, as well as aberrant gene silencing in cancer cells. Like a previously identified cell type-specific gene maspin, 14-3-3sigma is a p53-inducible gene; however, it participates in G2/M arrest in response to DNA-damaging agents. 14-3-3Sigma expression is restricted to certain epithelial cell types, including breast and prostate, whereas expression is absent in nonepithelial tissues such as fibroblasts and lymphocytes. In this report, we show that in normal cells expressing 14-3-3sigma, the 14-3-3sigma CpG island is unmethylated; associated with acetylated histones, unmethylated histone H3 lysine 9; and an accessible chromatin structure. By contrast, normal cells that do not express 14-3-3sigma have a methylated 14-3-3sigma CpG island with hypoacetylated histones, methylated histone H3 lysine 9, and an inaccessible chromatin structure. These findings extend the spectrum of cell type-specific genes controlled, partly, by normal epigenetic mechanisms, and suggest that this subset of genes may represent important targets of epigenetic dysregulation in human cancer.

14-3-3 Proteins↗

PubMed2005

Epigenetic analysis of HIC1, CASP8, FLIP, TSP1, DCR1, DCR2, DR4, DR5, KvDMR1, H19 and preferential 11p15.5 maternal-allele loss in von Hippel-Lindau and sporadic phaeochromocytomas.

Phaeochromocytoma is a neural-crest-derived tumour that may be a feature of several familial cancer syndromes including von Hippel-Lindau (VHL) disease, multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis type 1 (NF1) and germline succinate dehydrogenase subunit (SDHB and SDHD) mutations. However the somatic genetic and epigenetic events that occur in phaeochromocytoma tumourigenesis are not well defined. Epigenetic events including de novo promoter methylation of tumour-suppressor genes are frequent in many human neoplasms. As neuroblastoma and phaeochromocytoma are both neural-crest-derived tumours, we postulated that some epigenetic events might be implicated in both tumour types and wished to establish how somatic epigenetic alterations compared in VHL-associated and sporadic phaeochromocytomas. We identified frequent aberrant methylation of HIC1 (82%) and CASP8 (31%) in phaeochromocytoma, but both genes were significantly more methylated in VHL phaeochromocytomas than in sporadic cases. Of four tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptors analysed, DR4 was most commonly methylated (41%; compared with DcR2 (26%), DcR1 (23%) and DR5 (10%)). Gene methylation patterns in phaeochromocytoma and neuroblastoma did not differ significantly suggesting overlapping mechanisms of tumourigenesis. We also investigated the role of 11p15.5-imprinted genes in phaeochromocytoma. We found that in 10 sporadic and VHL phaeochromocytomas with 11p15.5 allele loss, the patterns of methylation of 11p15.5-differentially methylated regions were consistent with maternal, rather than, paternal chromosome loss in all cases (P<0.001). This suggests that 11p15.5-imprinted genes may be implicated in the pathogenesis of both familial (germline VHL and SDHD mutations) and sporadic phaeochromocytomas.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Genetics and epigenetics in major psychiatric disorders: dilemmas, achievements, applications, and future scope.

No specific gene has been identified for any major psychiatric disorder, including schizophrenia, in spite of strong evidence supporting a genetic basis for these complex and devastating disorders. There are several likely reasons for this failure, ranging from poor study design with low statistical power to genetic mechanisms such as polygenic inheritance, epigenetic interactions, and pleiotropy. Most study designs currently in use are inadequate to uncover these mechanisms. However, to date, genetic studies have provided some valuable insight into the causes and potential therapies for psychiatric disorders. There is a growing body of evidence suggesting that the understanding of the genetic etiology of psychiatric illnesses, including schizophrenia, will be more successful with integrative approaches considering both genetic and epigenetic factors. For example, several genes including those encoding dopamine receptors (DRD2, DRD3, and DRD4), serotonin receptor 2A (HTR2A) and catechol-O-methyltransferase (COMT) have been implicated in the etiology of schizophrenia and related disorders through meta-analyses and large, multicenter studies. There is also growing evidence for the role of DRD1, NMDA receptor genes (GRIN1, GRIN2A, GRIN2B), brain-derived neurotrophic factor (BDNF), and dopamine transporter (SLC6A3) in both schizophrenia and bipolar disorder. Recent studies have indicated that epigenetic modification of reelin (RELN), BDNF, and the DRD2 promoters confer susceptibility to clinical psychiatric conditions. Pharmacologic therapy of psychiatric disorders will likely be more effective once the molecular pathogenesis is known. For example, the hypoactive alleles of DRD2 and the hyperactive alleles of COMT, which degrade the dopamine in the synaptic cleft, are associated with schizophrenia. It is likely that insufficient dopaminergic transmission in the frontal lobe plays a role in the development of negative symptoms associated with this disorder. Antipsychotic therapies with a partial dopamine D2 receptor agonist effect may be a plausible alternative to current therapies, and would be effective in symptom reduction in psychotic individuals. It is also possible that therapies employing dopamine D1/D2 receptor agonists or COMT inhibitors will be beneficial for patients with negative symptoms in schizophrenia and bipolar disorder. The complex etiology of schizophrenia, and other psychiatric disorders, warrants the consideration of both genetic and epigenetic systems and the careful design of experiments to illumine the genetic mechanisms conferring liability for these disorders and the benefit of existing and new therapies.

Brain↗

PubMed2005

Epigenetic events in medulloblastoma development.

Over the last decade, the analysis of genetic defects in primary tumors has been central to the identification of molecular events and biological pathways involved in the pathogenesis of medulloblastoma, the most common malignant brain tumor of childhood. Despite this, understanding of the molecular basis of the majority of cases remains poor. In recent years, the emerging field of epigenetics, which describes heritable alterations in gene expression that occur in the absence of DNA sequence changes, has forced a revision of the understanding of the mechanisms of gene disruption in cancer. Accumulating evidence indicates a significant involvement for epigenetic events in medulloblastoma development. Recent studies have identified a series of candidate tumor suppressor genes (for example, RASSF1A, CASP8, and HIC1) that are each specifically epigenetically inactivated in a large proportion (> 30%) of medulloblastomas by promoter hypermethylation, leading to the silencing of their gene expression. These findings shed new light on medulloblastoma and offer great potential for an improved understanding of its molecular pathology. The authors review the current understanding of epigenetic events in cancer and their contribution to medulloblastoma development. Their nature, origins, and functional role(s) in tumorigenesis are considered, and the authors assess the potential utility of these events as a basis for novel diagnostic and therapeutic approaches.

Animals↗

PubMed2006

Epigenetic remodeling of the IL-2 and IFN-gamma loci in memory CD8 T cells is influenced by CD4 T cells.

Memory T cells (T(M)) are able to rapidly exert effector functions, including immediate effector cytokine production upon re-encounter with Ag, which is critical for protective immunity. Furthermore, this poised state is maintained as T(M) undergo homeostatic proliferation over time. We examined the molecular basis underlying this enhanced functional capacity in CD8 T(M) by comparing them to defective CD8 T(M) generated in the absence of CD4 T cells. Unhelped CD8 T(M) are defective in many functions, including the immediate expression of cytokines, such as IL-2 and IFN-gamma. Our data show that this defect in IL-2 and IFN-gamma production is independent of clonal selection, functional avidity maturation, and the integrity of proximal TCR signaling, but rather involves epigenetic modification of these cytokine genes. Activated Ag-specific CD8 T cells exhibit rapid DNA demethylation at the IL-2 and IFN-gamma loci and substantial histone acetylation at the IFN-gamma promoter and enhancer regions. These epigenetic modifications occur early after infection at the effector stage and are maintained through memory development. However, activated unhelped CD8 T cells, which fail to develop into functional memory and are incapable of rapid cytokine production, exhibit increased DNA methylation at the IL-2 promoter and fail to acetylate histones at the IFN-gamma locus. Thus, CD4 T cell help influences epigenetic modification during CD8 T(M) differentiation and these epigenetic changes provide a molecular basis for the enhanced responsiveness and the maintenance of a "ready-to-respond" state in CD8 T(M).

Acetylation↗

PubMed2006

Epigenetics and cancer: altered chromatin remodeling via Snf5 loss leads to aberrant cell cycle regulation.

The term 'epigenetics' refers to heritable changes in gene function that occur in the absence of any change in DNA sequence. Perturbations of epigenetic gene regulation may play a critical role in the genesis of most, if not all, cancers. These alterations include changes in covalent modifications of DNA and histones as well as non covalent changes in nucleosome positioning. Covalent epigenetic modifications have been the main focus of cancer investigation, perhaps because they are more readily assayed and understood than non covalent modifications. Recently, evidence has emerged demonstrating that perturbation of complexes that remodel the structure of chromatin by mobilizing nucleosomes may have a key role in tumor suppression and oncogenic transformation. For example, Snf5 (Ini1/Baf47/Smarcb1), a core component of the Swi/Snf ATPase chromatin remodeling complex, is a potent tumor suppressor that is specifically inactivated in lethal childhood cancers. Notably, these cancers may serve as a paradigm for epigenetic cancers as, despite their extremely aggressive nature, the majority have an entirely normal karyotype with only microdeletions at the Snf5 locus. Recent investigations have shed light upon the mechanistic basis of Snf5 function by demonstrating that Snf5 and the Swi/Snf complex regulate the cell cycle and cooperate with p53 to prevent oncogenic transformation.

Animals↗

PubMed2006

Epigenetic information in chromatin: the code of entry for DNA repair.

Epigenetic changes are important etiological factors of human cancer. Epigenetic information in chromatin (known as 'histone code') is a fascinating feature used by cells to extend and modulate the genetic (DNA) code. The histone code is thus proposed to be 'read' by cells to regulate accessibility to, and functions of, chromatin DNA. While the role of the epigenetic code involving chromatin modifying/remodeling complexes in transcriptional regulation is well established, it is only recently that these mechanisms have been implicated in DNA damage detection and DNA repair. However, how the components of the DNA damage sensing and repair machinery gain access to broken DNA in compacted chromatin remains a mystery. Recent studies provide important insights into DNA damage- and repair-specific modifications to histones and shed light on how the epigenetic code controls DNA repair.

Animals↗

PubMedDate not supplied

[Epigenetic cell reactions induced by ionizing radiation].

The importance of radiation modification of epigenetic activity in the general mechanism of radiobiological reactions is proved. The inheritable epigenetic changes induced by irradiation are one of the basic reasons of formation of the remote radiation pathology. It is noted that epigenetic inheritable changes of cells have the determined character distinguishing them from mutation changes, being individual and not directed. It is underlined the ability of ionizing radiation to modify a level of spontaneous genetic instability inherited in a number of cell generations on the epigenetic mechanism.

Animals↗

PubMed2000

Epigenetic mechanisms of nickel carcinogenesis.

This article considers the mechanism of nickel carcinogenesis, focusing primarily on the epigenetic changes associated with exposure of cells to carcinogenic nickel compounds. We discuss the delivery of nickel in the cell and contrast the genetic and epigenetic changes that have occurred. Within the epigenetic effects, alteration in the levels of transcription factors, such as ATF-1, p53, HIF-1, HIF-1alpha, and NFkappaB, are considered. The relationship between nickel and calcium metabolism and the role it plays in nickel carcinogenesis is also considered, as are reactive oxygen species and the interactions of nickel with proteins. We discuss these epigenetic discussions in light of the effects that nickel has on inducing DNA methylation in cells. It is of interest that nickel induces both a variety of signaling pathways as well as genes that seem to be important for the survival of cancer cells. It is also interesting that the same genes induced or repressed by nickel are similarly overexpressed or not expressed in nickel-transformed cells. It is suggested that this may represent a selection process crucial to the nickel carcinogenesis process.

Acetylation↗

PubMedDate not supplied

[Epigenetic inheritance and its possible role in the evolution of plant species].

As it is clear now, the level of gene expression in eukariotes is determined mainly by chromatin composition. Chromatin structure of a particular gene (it is a complex item, which includes nucleosome positioning, histone modifications and non-histone chromatin proteins) can be modified externally and is able to be inherited mitotically and meiotically. Changes in chromatine structure are the basis of so called epigenetic inheritance that occurs without modification of DNA sequence. One of the most striking examples of epigenetic inheritance in plants is epimutations--stable for many generation's alleles of some genes that do not differ in primary DNA structure. Molecular basis of epimutations seems to be DNA metylation. Epimutations may be widely distributed in nature and affect some basis morphological features that have a systematic significance. Possibility of inheritance of acquired epigenetic modifications lead us to reconsider an idea of multipLe independent origins of some plant forms (or ecotypes) under action of similar external conditions. Different populations of the same species may in this case be unrelated and has no common ancestor. Species should be considered as invariant of multiple ways of origin. Wide distribution of polyploids amongst higher plants suggests effective mechanism of repression of multicopy genes. Each allopolyploidisation event is followed by repression of random set of parent genes via changes in its chromatin structure. As a result, in the limits of the same hybrid formula may arise different stable combinations of epigenetically controlled features of parent species. These combinations may be classified as different species of other taxa.

Adaptation, Physiological↗

PubMed2005

[Epigenetic phenomena of plant polyploids].

Epigenetic phenomena, heritable changes in phenotype, and hence in gene regulation, but not in DNA sequence, occur in the process of polyploidization in many plants. These phenomena include gene silencing, DNA methylation, nucleolar dominance, transposable elements activation and genomic imprinting. Epigenetic phenomena might be caused by gene silencing or alternative gene expression from intergenomic interaction. These could also be induced from the changes of histone coding, without DNA methylation. Furthermore, hypomethylation, chromatin reconstitution or transposable element activation could contribute to epigenetic phenomena. These modifications may give rise to the diversification of gene expressing, to the genetic and cytological diploidization, as well as to intergenomic coordination. This paper reviews epigenetic phenomena in many plants and their influence on evolution of plant genome, thus hint the likely pathway of research in this field.

DNA Transposable Elements↗

PubMed2002

[The meaning of epigenetics].

Epigenetics, the term was introduced by Conrad H.Waddington, in 1942,he said that to compare genetics with epigenetics, the study of the processes by which genotype gives rise to phenotype. In 1987, Robin Holliday redefined epigenetic as "Nuclear inheritance which is not based on differences in DNA sequence". The author of this paper introduced that in Science,10 August 2001,there was a special collection of review articles focused on the topic of epigenetics. The new "histone code" hypothesis states that the highly modifiable amino termini could carry their own combinatorial codes to help control phenotype,and that part of this code is heritable. And in light of this hypothesis,researchers are approaching further possibilities in human biology and types of cancer and other diseases.

English Abstract↗

PubMed2005

[Progress of research on epigenetic and human disease.].

In the past few fears, there has been a nascent convergence of scientific understanding of human disease with epigenetic. Identified epigenetic processes involved in human disease include chromatin remodeling, genomic imprinting, X chromosome inactivation, and noncoding RNAs regulation. These processes influence chromatin structure and thereby regulate gene expression on the chromosome level or a cluster of linked genes level. Deregulation of these processes result in lots of disease which are characterized by complex patterns of mutations and associated phenotypes affecting pre- and postnatal growth, development, and neurological function. Epigenetic diseases are illustrated by the array of multi-system disorders and neoplasias and investigations of these diseases have an impact on biomedical research and provide interesting models for functions and mechanisms of epigenetic gene control.

Chromatin Assembly and Disassembly↗

PubMed2005

[Mechanisms of epigenetic reprogramming in Mammalian resonstructed embryos produced by nuclear transfer.].

Circumstantial studies indicated that incomplete or inappropriate epigenetic reprogramming of donor nuclei was likely to be the primary reason for failures in nuclear transfer. In this view, we discussed the roles of several epigenetic mechanisms, including DNA methylation, chromatin remodeling, imprinting and X chromosome inactivation, telomere maintenance, and epigenetic inheritance in the observed abnormalities in clones from different species. Understanding the mechanisms underlying epigenetic reprogramming control will help us resolve the inherent problems in nuclear transfer technology and make its applications promising.

Active Transport, Cell Nucleus↗

PubMed1984

Genetic and epigenetic control of connective tissues in the craniofacial structures.

The connective tissues of the craniofacial region can neither develop nor be maintained independently of their local environment. I have stressed such epigenetic control in the present brief review of the origin, differentiation, morphogenesis, and growth of selected craniofacial tissues. I began by discussing the origin of these tissues in the neural crest. The extensive migration of neural crest cells to form the craniofacial region of the embryo is epigenetically regulated by extracellular matrix products such as fibronectin, and by basal laminae of the epithelia along which some cells migrate. The trigger which initiates differentiation of these mesenchymal cells is provided by epithelia with which they come into contact either before, during, or after migration, as illustrated by the differentiation of both Meckel cartilage and mandibular dermal bones. Subsequent differentiation of secondary cartilage is also shown to be epigenetically initiated, in this case by the mechanical environment created by muscle action. Both secondary cartilages on avian dermal bones and the condylar cartilage of the mammalian dentary are discussed. The interplay between genetic and epigenetic factors in morphogenesis and growth of craniofacial connective tissues is then very briefly discussed.

Animals↗

PubMed2025

Analog epigenetic memory revealed by targeted chromatin editing.

Cells store information by means of chromatin modifications that persist through cell divisions and can hold gene expression silenced over generations. However, how these modifications may maintain other gene expression states has remained unclear. This study shows that chromatin modifications can maintain a wide range of gene expression levels over time, thus uncovering analog epigenetic memory. By engineering a genomic reporter and epigenetic effectors, we tracked the gene expression dynamics following targeted perturbations to the chromatin state. We found that distinct grades of DNA methylation led to corresponding, persistent gene expression levels. Altering the DNA methylation grade, in turn, resulted in permanent loss of gene expression memory. Consistent with experiments, our chromatin modification model indicates that analog memory arises when the positive feedback between DNA methylation and repressive histone modifications is lacking. This discovery will lead to a deeper understanding of epigenetic memory and to new tools for synthetic biology.

Epigenesis, Genetic↗

PubMed2026

Epigenetic age acceleration is not strongly associated with cardiorespiratory fitness in heart failure: a pilot study.

BACKGROUND: In heart failure (HF), standard measures such as left ventricular ejection fraction and cardiopulmonary exercise testing incompletely capture interindividual differences in disease status or prognosis. DNA methylation (DNAm) epigenetic clocks, which estimate biological age and epigenetic age acceleration (EAA), may provide complementary insight into cardiorespiratory fitness and systemic aging in HF. RESEARCH DESIGN AND METHODS: We analyzed peripheral blood DNAm from fourteen patients enrolled in REDHART2, a clinical trial of interleukin-1 blockade following hospitalization for acute systolic HF. Genome-wide DNAm was assayed using Illumina EPIC arrays and several clocks were applied to these data. Associations between biological age or EAA and cardiorespiratory fitness measures, inflammatory markers, and clinical parameters were evaluated. RESULTS: All epigenetic clocks demonstrated moderate to strong correlations with chronological age. Biological age was consistently associated with measures of cardiorespiratory fitness, particularly oxygen consumption normalized to fat free mass (VO2_FFM). However, chronological age showed similar associations, and biological age did not significantly improve prediction of VO2 parameters beyond chronological age alone. EAA was not significantly associated with cardiorespiratory fitness for any clock. CONCLUSIONS: In this pilot study, neither biological age nor EAA provided significant predictive value beyond chronological age for cardiorespiratory fitness in patients with HF. CLINICAL TRIAL REGISTRATION NUMBER: NCT03797001.

DNA methylation↗